Antioxidant, Anti-Inflammatory, and Microbial-Modulating Activities of Nutraceuticals and Functional FoodsView this Special Issue
Review Article | Open Access
Antioxidant, Immunomodulating, and Microbial-Modulating Activities of the Sustainable and Ecofriendly Spirulina
The highly nutritional and ecofriendly Spirulina (Arthrospira platensis) has hypolipidemic, hypoglycemic, and antihypertensive properties. Spirulina contains functional compounds, such as phenolics, phycocyanins, and polysaccharides, with antioxidant, anti-inflammatory, and immunostimulating effects. Studies conducted on Spirulina suggest that it is safe in healthy subjects, but attitude to eating probably affects the acceptability of Spirulina containing foods. Although the antioxidant effect of Spirulina is confirmed by the intervention studies, the concerted modulation of antioxidant and inflammatory responses, suggested by in vitro and animal studies, requires more confirmation in humans. Spirulina supplements seem to affect more effectively the innate immunity, promoting the activity of natural killer cells. The effects on cytokines and on lymphocytes’ proliferation depend on age, gender, and body weight differences. In this context, ageing and obesity are both associated with chronic low grade inflammation, immune impairment, and intestinal dysbiosis. Microbial-modulating activities have been reported in vitro, suggesting that the association of Spirulina and probiotics could represent a new strategy to improve the growth of beneficial intestinal microbiota. Although Spirulina might represent a functional food with potential beneficial effects on human health, the human interventions used only supplements. Therefore, the effect of food containing Spirulina should be evaluated in the future.
Spirulina (Arthrospira platensis) is a microscopic and filamentous cyanobacterium that has been suggested as a sustainable and ecofriendly microalga useful for bioremediation, nitrification, and carbon dioxide (CO2) fixation. In the context of the bioremediation, Spirulina is considered a candidate for the removal of toxicants, such as heavy metals [1–5] and phenol . Besides, within microalgae and cyanobacteria Spirulina showed maximum biomass productivity with the highest CO2 fixation rate  and it has been suggested for the nitrification from urine in urban wastewaters . The environmentally friendly Spirulina does not need fertile land, has a rapid growth, and takes less energy input and less water per kilogram than soya and corn proteins . Due to its cost-effective and high nutritional value Spirulina has been used as protein-rich animal feed for improving meat production and quality  and has been proposed as a sustainable approach to prevent Protein Energy Malnutrition (PEM) and Protein Energy Wasting (PEW) in humans .
On the other hand, Spirulina presents hypolipidemic , hypoglycemic , and antihypertensive  properties. Studies in rats suggested that Spirulina increases the lipoprotein lipase activity  and the pancreatic secretion of insulin . The latter effect was observed also in mice treated with phycocyanin isolated from Spirulina and was accompanied by a decrease in cholesterol, triglycerides, and malondialdehyde (MDA) and by an increase in the serum total antioxidant capacity . On the other hand, the oral administration of an antihypertensive peptide, purified by Spirulina and resistant to in vitro digestion by gastrointestinal proteases, decreased both systolic (SBP) and diastolic (DBP) blood pressure in spontaneously hypertensive rats .
All these effects could be considered useful in the prevention of the metabolic syndrome. In fact, according to the World Health Organization (WHO), high serum triglyceride level, low serum high-density lipoprotein (HDL) cholesterol level, hypertension, and elevated fasting blood glucose are four of the five risk factors (three out of the five required) for the diagnosis of metabolic syndrome . Metabolic syndrome is associated with subclinical low grade inflammation, oxidative stress, and intestinal dysbiosis and it has been suggested that the gut microbiota could be a target for nutraceuticals . In this regard, in vitro antimicrobial activity [19–21] and the capacity to improve the growth of probiotics [22–24] have been reported for Spirulina.
Furthermore, Spirulina contains many functional bioactive ingredients with antioxidant and anti-inflammatory activities, including phenolic phytochemicals [25, 26] and the phycobiliprotein C-phycocyanin .
We aimed to evaluate the possibility that Spirulina could be an antioxidant and immunomodulating functional food by reviewing the human evidences, after taking into account safety and acceptability aspects.
2. Functional Compounds of Spirulina
Spirulina has high nutritional values due to its content in proteins, essential amino acids, minerals, essential fatty acids, vitamins, and liposoluble antioxidants (vitamin E and carotenoids) [28–38] (Table 1).
Great attention has been given to Spirulina antioxidant and anti-inflammatory activities in many animal species [16, 34, 38–50] that could not be explained only by Spirulina macro and micronutrient content (Table 1).
It has been suggested that the antioxidant activity accounts for the protective role of Spirulina against the toxicity induced by carbon tetrachloride (CCl4) , by metals (arsenic, mercuric chloride, chromium, cadmium, and fluoride) [34, 41–44], by the insecticide deltamethrin in mice  and rats , and by the drugs tilmicosin (in mice) , gentamicin (in rats) , and erythromycin in Egyptian Baladi bucks (Capra hircus) .
Furthermore, antioxidant effects of Spirulina have been reported also in murine models of inflammation [48–50]. In rat models of experimental colitis (acetic-acid induced)  and arthritis (Freund’s adjuvant-induced  and collagen-induced ) the antioxidant activity of Spirulina was associated with anti-inflammatory effects. Abdel-Daim et al.  recently observed a decrease of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) in serum and at the same time an improvement of oxidative stress markers [malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and glutathione peroxidase (GPX)] in hepatic, renal, and brain tissues, by using Spirulina platensis powder (500 and 1000 mg/kg) 1 h before deltamethrin (15 mg/kg) in mice .
Hu et al.  suggested a potential concerted modulation of nuclear factor-erythroid 2-related factor 2 (Nfr2)/antioxidant responsive elements (ARE) and nuclear factor-kappa B (NF-kB) in inflammation and carcinogenesis. Many phenolic antioxidants [52, 53] and C-phycocyanin [54, 55] exert their anti-inflammatory and antioxidant effects through the integrated modulation of Nrf2 and NF-kB pathways. In particular, C-phycocyanin was able to inhibit NF-kB  and induced Nrf2 activation in pancreatic β-cell INS-1 . Although Spirulina antioxidant and anti-inflammatory activities can be due to both phenolic compounds and phycocyanins, C-phycocyanin is contained in higher amounts (Table 1) and has been studied more in vitro [56–63] and in animal models [27, 57, 64–66]. In addition to the scavenging property of C-phycocyanin [56, 57], in cellular models it exerted the antioxidant activity also regulating the antioxidant enzymes activity, such as SOD, CAT, and GPX  and inhibiting the cyclooxygenase-2 (COX-2)  and the inducible nitric oxide synthase (iNOS) gene expression . Furthermore, a 50% inhibitory concentration (IC50) of 180 nM has been found in a COX-2 isolated enzyme assay . The effects of C-phycocyanin on COX-2 [64, 65] and iNOS  were also confirmed in animals, where a decrease of the proinflammatory TNF-α expression in the carragenan-induced rat paw  and of the TNF-α and interleukin-1β (IL-1β) expression in the cochlea and inferior colliculus after salicylate-induced tinnitus in mice was observed . Also Spirulina lipid extract  has been shown to repress proinflammatory cytokine (TNF-α, IL-1β, and IL-6) expression and secretion via inhibition of NF-kB pathway. Besides, Spirulina contains also heptadecane, a volatile component which has been shown to suppress proinflammatory gene expressions by reducing NF-kB activity . However, it must be taken into account that polysaccharides  contained in Spirulina (Table 1) can induce NF-kB pathway. In particular, the high molecular weight polysaccharide Immulina has been reported have immunostimulatory activity [70–72] and increased IL-1β and TNF-α expression by inducing NF-kappa B pathway . Despite the fact that the immunostimulatory activity could increase inflammation, it must be taken into account that in syngeneic tumor-implant mice (C57BL/6 versus B16 melanoma) the antitumor activity and the increased NK cytotoxicity were observed in parallel with the production of interferon-gamma (IFN-γ) . Furthermore, it was also observed that Spirulina consumption increased macrophage activation (phagocytic activity and nitrite production) in chicken . Therefore, Spirulina could modulate immune function, reducing inflammation without inhibiting the innate immune defences.
3. Microbial-Modulating Activities
It has been recently reported that, in the majority of commercially available Spirulina food supplements, Arthrospira platensis was the predominant taxon (81.2–100.0%) among the cyanobacteria .
Spirulina (Arthrospira) platensis is able to inhibit the growth of some Gram-negative (Escherichia coli, Pseudomonas aeruginosa, and Proteus vulgaris) and Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Bacillus pumulis) . In fact, Spirulina produces extracellular metabolites with antibacterial activity (Figure 1) [19–21, 77]. The methanol extract from grown culture medium of Spirulina showed a higher antimicrobial activity than hexane , dichloromethane [20, 21], petroleum ether , ethyl acetate [20, 21] extracts, and volatile components (heptadecane and tetradecane) , especially against Streptococcus faecalis , Staphylococcus epidermidis  and Candida albicans , Gram-positive bacterium Staphylococcus aureus , and Gram-negative bacterium Escherichia coli .
On the contrary, low (minimum inhibitory concentrations, MIC ≥ 512 μg/ml) or no inhibitory effect was found against other bacteria (Pseudomonas aeruginosa, Salmonella typhirium, and Klebsiella pneumoniae) . El-Sheekh et al.  purified an antimicrobial compound (molecular formula C15H18NO8) from Spirulina platensis with no characteristic odor and yellowish green color. This extract (soluble in methanol, diethyl ether, chloroform, and dimethyl sulfoxide, but sparingly soluble in water and acetone) was active against the unicellular fungus Candida albicans (MIC = 30 μg/ml) and the Gram-positive Bacillus subtilis (MIC = 60 μg/ml) at lower concentrations in comparison to the effect against the Gram-negative bacterium Pseudomonas aeruginosa (MIC = 85 μg/ml) . Besides, Spirulina has been recently used in the synthesis of biofunctionalized gold nanoparticles with antibacterial activity against Gram-positive organisms (Bacillus subtilis and Staphylococcus aureus) . Therefore, the research on advanced medical applications of Spirulina-derived products in the treatment of infectious diseases caused by Gram-positive organisms is growing (Figure 1).
On the other hand, it has also been reported that extracellular products of Spirulina, obtained from a culture in late exponential stage and separated by filtration, significantly promote the in vitro growth of the lactic acid bacteria (Lactococcus lactis, Streptococcus thermophilus, Lactobacillus casei, Lactobacillus acidophilus, and Lactobacillus bulgaricus) . Probiotics, including the genera Lactobacillus and Bifidobacterium (Figure 1) , are largely used as starter bacteria for the production of yogurt , the most popular fermented diary product worldwide. Spirulina biomass has a stimulatory effect on the growth (during fermentation) and/or increases the survival (during storage) of Bifidobacterium [23, 24], Lactobacillus acidophilus [24, 76], Lactobacillus bulgaricus [79–81], Lactobacillus casei , and Streptococcus thermophilus [23, 76, 79, 80, 82].
Although the better growth and survival have been attributed to the high level of nitrogenous substances, in particular free amino acids, in the Spirulina biomass , also phenolic compounds have been shown to exert antimicrobial or bacteriostatic activities, as well as improving the growth of probiotics . Therefore, the complex composition of Spirulina could improve the quality of fermented diary products and the supplementation with Spirulina might represent an alternative strategy to the synbiotics formulations. The latter appear more effective than probiotics alone in the prevention of the dysbiosis (Figure 1) associated with immune-mediated, inflammatory, and dysmetabolic diseases .
Despite the rich literature on in vitro effect of Spirulina, only few studies have been conducted in vivo. Although in mice the gut microbiota of the Spirulina-fed group was 70% similar to that of the control mice , changes of gut microbiota ecology induced by Spirulina feeding in mice have been showed by Rasmussen and collegues . The authors observed that Spirulina plantensis leads change to gut microbiota composition in mice reducing Bifidobacterium animalis and increasing Clostridium irregulare, suggesting that numbers of this organism are modified through both blue-green algae supplements . It is largely established that drastic changes of microbiota composition occur in several gastrointestinal, immunological, and metabolic diseases [111, 112]. In many microbiota related diseases, including Inflammatory Bowel Disease (IBD), it is well known that a strong unbalanced ratio among the genera of potentially protective bacteria and normal anaerobic bacteria is present. In particular, Bacteroides sp., Eubacterium sp., and Lactobacillus sp are significantly decreased . All these evidences suggest that Spirulina may be useful to improve animal and human health changing the gut microbiota composition and promoting beneficial batcterial growth.
4. Safety and Acceptability
The Food and Drug Administration (FDA) has categorized Arthrospira products as “generally recognized as safe” (GRAS) for human consumption and the Dietary Supplements Information Expert Committee (DSI-EC) concluded that there is not a serious risk to health with consumption of Spirulina .
Reported side effects associated with Spirulina consumption are insomnia and gastric problems with uncertain or unlikely causality  and only few cases of severe side effects have been reported, including a case of rhabdomyolysis after the consumption of 3 g/day for 1 month . Two cases of anaphylaxis caused by Spirulina tablets were reported [116, 117] of which one in a 17-year-old male who had a history of atopic dermatitis, asthma, allergic rhinitis, and a possible pollen-food syndrome (oral allergy symptoms to tomato and cucumber) . Three cases of autoimmune-mediated skin damage were reported, of which one in a 82-year-old woman , whereas the other two cases were observed in subjects consuming Spirulina as ingredient of multicomponent-nutraceuticals (organic cayenne pepper, ethylsulfonylmethane, and the algae Aphanizomenon flos-aquae and Spirulina or Ginseng, Ginkgo biloba, and Spirulina) . In this regard, it is well known that plant-food and herbal supplements could have adverse effects, such as hepatotoxicity and autoimmune hepatitis . Besides, the two cases described by Lee and Werth  involved a 57-year-old man with known pemphigus vulgaris and a 45-year-old woman with a history of hypertension, chronic migraines and fibromyalgia. Furthermore, a case report of hepatotoxicity involved a 52-year-old Japanese man who had a history of hypertension, hyperlipidemia and type 2 diabetes (T2D) and taking medications (amlodipine besilate, simvastatin, and acarbose) . In this context, potential food-drug interactions have been hypothesized for Spirulina  and for phenolic phytochemicals [123–125]. Therefore, Spirulina should be ingested with caution in subjects with diseases, in particular in patients in treatment with substrates of cytochrome P450 enzymes, such as immunosuppressant, antihypertensive, and lipid lowering drugs [121–125].
Although Spirulina can be considered safe in healthy subjects, sensory characteristics of a functional food are important in the consumer acceptance of the product.
Table 2 shows the studies that have investigated the overall acceptability of foods with Spirulina, including baby formulas, pomegranate juices, biscuits, snacks, pasta, ice creams, yogurt, and acidophilus milks [32, 36, 85–92]. The number of panelists ranged between 4 and 43, and the point scale was different between studies (Table 2). Only a study on functional biscuits containing Spirulina or phycocyanin isolated from Spirulina reported similar levels of acceptability versus control . In the other studies, both higher and lower levels of acceptability were reported (Table 2). The results were affected by the type of product, by the percentage of Spirulina and by the type of panelists.
|SFV = spirulina with fruits and vegetables-based baby food formula; SCP = spirulina with cereals-based baby food formula; = numbers; PS = point scale.|
Baby food formulas with added Spirulina had an overall acceptability scores in the range from 82.72 to 96.37 and the trained panelists assigned the high scores to products with Spirulina 5% .
No significant differences were noticed by semitrained panelists between the pomegranate juices and formulate pomegranate beverage with Spirulina (4%) and Echinacea (6%) extracts (sweetened by stevioside 5%) in appearance, color, odors, and consistency, while the other parameters including taste and overall acceptability showed a significant decrease in the mean values of pomegranate juice compared to the fresh formulate pomegranate beverage .
Trained panelists gave a higher score to a snack with 2.5% of Spirulina, but the addition of 7.5% or more decreased the acceptability . The percentage of Spirulina in pasta considered acceptable is different in trained and untrained panelists. In particular, pasta with a percentage of Spirulina maxima up to 2% was preferred by untrained panelists compared to control pasta , whereas the most preferable one by trained panelists  was the pasta enriched with 10% Spirulina platensis. The latter was not acceptable for consumers  who considered less acceptable also pasta produced with integral wheat flour. The percentage of Spirulina that did not decrease the acceptability is lower for ice cream compared with supplemented pasta (Table 2). A panel of judges considered ice cream with 0.15% of Spirulina a superior product when compared to 0% and 0.075% ice creams, due to the light green (pistachio) color, but the intense green color decreased overall acceptability of the ice cream with 0.23% and 0.3% of Spirulina . On the contrary, yogurt with Spirulina 0.3% had a higher score compared to 0%, 0.1%, 0.2, and 0.5% of Spirulina . Malik et al.  suggested that the lower score at 0.1% level when compared to control may be attributed to dull color and appearance and less acidic flavor which is essential for acceptability of yogurt, whereas the low acceptability of the 0.5% can be due to increased acidity and intense green color. It is well known that Spirulina causes decrease in pH of yogurts, due to its effect on Lactobacilli growth and viability [82, 126]. Guldas and Irkin , with trained panelists who did not assign excessive sour taste to acidophilic yogurt, reported that the 0.5% of Spirulina powder addition was more acceptable than 1%, due to the slightly greenish color and algal flavor of the latter compared to the former. Therefore, different sensory expectations, experiences, knowledge, learning, and attitude to eat affect the overall acceptability [127, 128].
5. From Nutritional Supplement to Antioxidant and Immunomodulating Functional Food in Humans
Due to its high nutritional value, Spirulina has been used for treatment of anemia and malnutrition in undernourished children [28, 29, 129] and disease patients [29, 103, 130, 131]. Positive effects of Spirulina at doses ranging between 1 g/day  and 200 g/day  against anemia have been reported in children [28, 29, 129], runners , senior citizens , patients with pathologies such as nonalcoholic fatty liver disease (NAFLD) , T2D , or HIV-infected [29, 103]. Only two studies did not find improvement in Hemoglobin (Hb) levels after Spirulina supplementation. In the first study (Spirulina 6 g/day, 30 days), Hb was measured only in a subgroup of 5 subjects, probably not enough to reach statistical significance . In the second study, both supplemented and control groups received also dietary products supplied by the World Food Program (WFP) and showed improvement of protidemia . Besides in HIV-infected patients [29, 103] and undernourished children [28, 29] increases in body weight were reported, probably due to protein content. In agreement with this hypothesis, in HIV-infected antiretroviral-naïve patients an increase in fat free mass (FFM) has been observed versus soya supplementation . On the other hand, Spirulina did not affect body weight in subjects with dyslipidemia . In this context, Spirulina reduced plasma lipids concentrations in many studies [12, 13, 100, 106, 108, 130, 134–137]. Accordingly, the results of a recent meta-analysis  of 7 Randomized Controlled Trials (RCT) showed a significant effect of supplementation with Spirulina in reducing plasma concentrations of total cholesterol (−46.76 mg/dL, < 0.001), low density lipoprotein (LDL) cholesterol (−41.32 mg/dL, < 0.001), and triglycerides (−44.23 mg/dL, < 0.001) and elevating those of HDL cholesterol (+6.06 mg/dL, = 0.001). In overweight subjects  and in T2D patients with dyslipidemia  the improvement in the lipid profile was accompanied by a reduction of blood pressure. Furthermore, some studies found also decreased levels of glucose or HOMA-IR after Spirulina supplementation in healthy volunteers , in subjects with NAFLD , T2D , and HIV-infected antiretroviral-naïve patients [102, 135].
Table 3 summarizes the 17 studies [29, 93–108] that investigated the effect of long term consumption (duration range: 7 days –12 months ) of Spirulina or Spirulina-derived Immulina on markers of immune and redox status.
| = numbers; drink containing β Carotene 7600 mcg, vitamin A 400 IU, vitamin E 80 IU, vitamin C- 320 mg, zinc-2.7 mg, and selenium-40 mcg; groups received also dietary products supplied by the World Food Program (WFP); BCG-CWS: cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guérin; CA: Candidaalbicans; CAT: catalase; Con A: concanavalin A; COPD: chronic obstructive pulmonary disease; GSH: glutathione; IL-: interleukin; MDA: malondialdehyde; PHA: phytohemagglutinin; ROOH: lipid hydroperoxides; SOD: superoxide dismutase; T2D: type 2 diabetes; TAS: total antioxidant status; TT: tetanus toxoid.|
The majority of the studies had a longitudinal (uncontrolled) or parallel design (controlled or uncontrolled), and only two studies followed a crossover design. The number of participants in individual trials was extremely variable, ranging from 8  to 169 , and characteristics of subjects varied between studies. In particular, healthy subjects, elderly, runners, children, patients with HIV infection, and T2D patients with allergic rhinitis or chronic obstructive pulmonary disease (COPD) were enrolled (Table 3).
Various biomarkers were used to monitor different aspects of redox and immune status in biological fluids and cells. Markers of redox status included total antioxidant status (TAS, ), vitamin C (vit. C, ), GSH (), antioxidant enzymes () (e.g., SOD, CAT, and GPX), and markers of lipid peroxidation () [e.g., MDA, thiobarbituric acid reactive substances (TBARS), and peroxides (ROOH)]. Markers of immune function included cytokines (), ex vivo cytokines’ production by peripheral blood mononuclear cells (PBMC) (), lymphocytes’ populations (), lymphocytes’ proliferation (), and NK cytotoxic activity ().
Unchanged NK, NKT, and T cells were found after Spirulina consumption in healthy subjects . Increases in T helper lymphocytes (CD4+ counts) were reported in HIV-infected patients (Table 3). In particular, the increase in CD4+ count was always accompanied by a decrease in the viral load [101–103]. This effect could be mediated by the antiviral activity against HIV of the natural sulfated polysaccharide (calcium spirulan), contained in Spirulina . Accordingly, the increase in lymphocytes was observed in HIV-positive, but not in HIV-negative undernourished children . Furthermore, Winter et al.  reported no effects on viral load with consequent progression of disease (e.g., decrease of CD4+ cells), in HIV patients, despite the increase in TAS. Also other three studies measured both redox and immune markers [98, 99, 106].
A recent study in elderly found a lower increase in the IL-2/IL-6 ratio in obese compared to normal weight (NW) after Spirulina supplementation . Furthermore, only in NW subjects an improvement of TAS and TBARS levels after treatment was observed . Also gender differences were found in elderly after Spirulina consumption, with increase of IL-2 and SOD in female and decrease of IL-6 accompanied by increase in TAS in males . The third study, conducted in T2D patients, found decreased MDA levels that were associated with decrease of IL-6 only in patients with dyslipidaemia . Therefore, the concerted modulation of redox and inflammatory status by Spirulina in humans requires more studies.
On the other hand, improvement of at least one marker of redox status (decrease in markers of peroxidation and/or increase in antioxidant enzymes, TAS, GSH, or vitamin C) was reported in healthy subjects (7.5 g/day, 3 weeks) , elderly (8 g/day, 12 and 16 weeks) [98, 99], runners (4 g/day, 2 weeks) , COPD (1 g and 2 g/day, 60 days) , and T2D (8 g/day, 12 weeks)  patients. Only Shyam et al.  reported decreased GSH and unchanged MDA, TAS, vitamin C, and SOD in healthy subjects after Spirulina (1 g/day, 30 days).
Concerning the ex vivo markers of immune function, NK cytotoxic activity increased after both 7 days  and 8 weeks  of Spirulina or Spirulina-derived Immulina supplementation, whereas data on proliferation of lymphocytes and cytokines’ production varied with the stimulus used (BCG-CWS: cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guérin; CA: Candida albicans; Con A: concanavalin A; PHA: phytohemagglutinin; or TT: tetanus toxoid) and the duration of supplementation (Table 3), also in the same study . In particular, after the Spirulina-derived Immulina 400 mg/day for 56 days, a significant correlation between age and the increase in TT-induced CD4+ proliferation was found, while significant correlations were not found with respect to CA response. On the other hand, no effect was observed on TT-induced proliferation of CD19+, whereas the CA-induced CD19+ proliferation was increased after 3–8 days but decreased at day 56. Also the effect on the production of cytokines was temporary. The CA- and TT-induced production of IL-5 a Th2-related cytokine was increased at the beginning of the supplementation (3–8 days) but was inhibited at 56 days. On the contrary, the CA- and TT-induced production of IL-4 was decreased at day 3 and no effect was observed on IL-10 response during all the supplementation period. Concerning Th1 cytokines, after 3, 8, and/or 14 days of consumption a significant increase was observed of the CA- and/or TT-induced production of TNF-α (3–8 days, CA and TT), IFN-γ (day 3 CA, 3–14 days TT), and IL-2 (only CA day 3 and day 56), whereas at day 56 the TT-induced productions of TNF-α and IFN-γ were decreased. Although both Th1 and Th2 improvements were temporary, the increase in IFN-γ could account for the increased NK activity observed in other studies with Spirulina or Spirulina-derived Immulina [94, 96].
Overall, Spirulina seems to affect more innate immunity than adaptative immunity, but the immunomodulating activity of Spirulina in humans requires further investigations.
Furthermore, in the majority of the studies the effect of Spirulina (Arthrospira) platensis or a Spirulina not specified species has been investigated and only in two studies Spirulina maxima has been used (Table 3). Therefore, more studies are needed in order to evaluate the possible specie-specific effects in humans.
The concerted modulation of antioxidant and inflammatory responses (by Nrf2 and NF-kB pathways), suggested by in vitro and animal studies (Table 1), requires more confirmation in humans (Table 3). It has been suggested that the temporary priming effect on the responses of peripheral Th1, Th2, and B cells to antigenic stimuli could be related to a proinflammatory effect of Immulina . However, the effects on cytokines and on lymphocytes’ proliferation are contrasting, depending on age, gender, and body weight differences. In this context, ageing , obesity [141, 142], and metabolic syndrome  are associated not only to chronic low grade inflammation, but also to immune impairment (recurrent infection and low vaccine efficacy). Therefore the increased immune response to antigenic stimuli could be protective in elderly .
On the other hand, Spirulina has hypolipidemic, hypoglycemic, and antihypertensive properties, useful in the prevention of the metabolic syndrome . In this context, the alteration of gut microbiota is common in elderly , obese , and subjects with the metabolic syndrome .
From that, the microbial-modulating activities of Spirulina (reported in vitro and in animal models, Figure 1) suggest that the association Spirulina and probiotics could represent a new synbiotic, maintaining and/or restoring the homeostasis at level of gut microbiota. Human intervention studies are required for confirmation of this hypothesis.
Furthermore, Spirulina improves oxidative stress markers and NK activity in healthy subjects and CD4+ count in HIV+ patients.
However, among bioactive molecules from Spirulina (Table 1) only Immulina has been tested in humans (Table 3). Therefore the role of bioactive molecules from Spirulina for human applications requires further studies. Moreover, despite the fact that Spirulina might represent a functional food with potential beneficial effects on human health, the human interventions used supplements (Table 3). Although the tested doses (1–20 g/day) in these studies (Table 3) were not greater than the maximum acceptable percentage (10%) of Spirulina in functional foods (Table 2), no data are available on the efficacy of Spirulina containing foods. Therefore, the healthy effect of food containing Spirulina should be further evaluated.
Besides, previous studies indicate that some antioxidant and immunological markers are sensitive to stimuli that affect the mood of the individual. In particular, the salivary TAC increased 30 minutes after the vision of a comical video  and pleasant emotions increase the salivary IgA and cortisol . In this context different species of Spirulina, possibly having different biological effects, showed different acceptability [87, 88]. Therefore, the study of the relationship between liking and markers of antioxidant and immune status should be considered in humans studies.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank Claudio Andrew Gobbi for English review of the manuscript.
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